CN114760987A

CN114760987A - Soluble polymeric ocular inserts with biodegradable polymers

Info

Publication number: CN114760987A
Application number: CN202080082362.3A
Authority: CN
Inventors: H·A·凯特尔森; R·兰加拉詹
Original assignee: Alcon Inc
Current assignee: Alcon Inc
Priority date: 2019-12-10
Filing date: 2020-12-08
Publication date: 2022-07-15
Also published as: JP2023503524A; US20220323346A1; MX2022007056A; KR20220084381A; JP7406634B2; AU2020400389B2; AU2020400389A1; EP4072521A1; WO2021116907A1; BR112022011067A2; US20210169781A1; US11395797B2; CA3161982A1; TW202122071A; US11779537B2

Abstract

The present application provides a polymeric ocular insert comprising: a biodegradable polymer and one or more mucoadhesive polymers that are biocompatible with the ocular surface and tear film of the eye, wherein the biodegradable polymer increases the dissolution time of the polymer ocular insert by at least 15% compared to a control polymer ocular insert that is otherwise identical except for the absence of the biodegradable polymer.

Description

Soluble polymeric ocular inserts with biodegradable polymers

Technical Field

The present disclosure relates generally to polymer ocular insert technology, and more particularly to dissolvable polymer ocular inserts with biodegradable polymers and which release lubricants and drugs into the eye (including but not limited to the anterior segment and the posterior segment) over a long duration of time as compared to topical drop dosage forms.

Background

Many ophthalmic formulations include compounds that provide lubricity and other desirable properties. When these formulations are instilled into the eye, the properties of such compounds may prevent undesirable problems such as bioadhesion and friction-induced tissue damage formation, and may promote natural healing and recovery of previously damaged tissue.

Compliance with the administration of topically applied ophthalmic formulations (such as liquids, ointments, gels, sprays) is often poor, particularly for the treatment of dry eyes, allergies, infections, and slowly progressing diseases (such as glaucoma), requiring multiple applications per day to lubricate and deliver drugs to the eye. Contact with topically applied aqueous formulations is generally determined by the short retention time of the formulation on the ocular surface, which may be less than 25 minutes after instillation. Paugh et al, Optom Vis Sci [ Vision science ], month 8, 2008; 85(8):725-31. Typical aqueous ophthalmic formulations can be diluted or rinsed off the ocular surface within minutes, causing a change in usage or resulting in a reduction in the accuracy and precision of the dosage administered to the eye. Therefore, there is a need to reduce the treatment burden and improve compliance.

Ointments and gels have high viscosity and generally stay in the eye longer than liquids, providing more accurate administration. However, they also interfere with the vision of the patient and may require a minimum of 2-3 administrations per day. For these and other reasons, outage rates can be high. Swanson, m., j.am.optom.assoc. [ american society for eye vision, 2011; 10:649-6.

Inserts (bioerodible and non-bioerodible) are also available and allow for less frequent administration. Pesciina et al, Drug Dev Ind Pharm [ Drug development and pharmacy ]; 7:1-8 in 5 months in 2017; karthikeyan, MB et al, Asian j. pharmacol [ Asian journal of pharmacology ]; 2008; month 10-12, month 192-. However, these inserts require complex and detailed preparation and may be uncomfortable for the patient. An additional problem with non-bioerodible inserts is that they must be removed after use. However, with proper use and adequate patient education, the insert would be an effective and safe treatment option for dry eye patients.

Hydroxypropyl cellulose ophthalmic inserts (e.g., hydroxypropyl cellulose ophthalmic inserts

(Aton Pharmaceuticals Inc.]) Have been used in dry eye patients. These inserts were translucent cellulose-based rods measuring 1.27mm in diameter and 3.5mm in length. Each of these inserts contained 5mg of hydroxypropyl cellulose, with no preservatives or other ingredients. The medication is administered by placing a single insert into the sub-ocular dome below the bottom of the meibomian plate. These inserts are particularly useful for patients who still have dry eye symptoms after adequate treatment with artificial tears. They are also suitable for patients with keratoconjunctivitis sicca, exposed keratitis, decreased corneal sensitivity, and recurrent corneal erosion. Multiple studies have been performed to evaluate the efficacy of HPC ophthalmic inserts. (Luchs, J et al, Cornea [ Cornea ]]2010; 1417-1427; eye Contact lenses (Koffler B et al)](ii) a 2010; 36: 170-; McDonald M et al, Trans Am Ophthalmol. Soc. [ Proc. Association of the American society for ophthalmology]2009; 107: 214-221; wander A and Koffler B, Ocul Surf [ eyeball surface ]]7 months in 2009; 7(3):154-62).

However, using these typesInserts also present challenges. For example,

the insert tends to dissolve slowly and may remain in the eye even after 15-20 hours. Due to the rod-like design, the rod is hard and inelastic, with edges. The slow dissolution characteristics coupled with the stick hardness and design may result in side effects including blurred vision, foreign body sensation and/or discomfort, eye irritation or congestion, hypersensitivity, photophobia, eyelid edema, and caking or drying of viscous materials on the eyelashes. The most common side effect of these hydroxypropyl cellulose ophthalmic inserts is blurred vision due to the long retention of the insert.

There are other approaches to develop polymeric ocular inserts that are comfortable, have longer dissolution times to release lubricants and drugs, and can improve patient compliance.

Disclosure of Invention

The present invention provides a polymeric ocular insert comprising:

a biodegradable polymer and one or more mucoadhesive polymers that are biocompatible with the ocular surface and tear film of the eye; and is

Wherein the biodegradable polymer increases the dissolution time of the polymer ocular insert by at least 15% compared to a control polymer ocular insert that is otherwise identical except for the absence of the biodegradable polymer.

The present invention also provides a method for treating an ocular disorder comprising applying a polymeric ocular insert according to embodiments of the present disclosure to the cul-de-sac of an eye.

The present invention is based in part on the following findings: the addition of a biodegradable polymer to a polymeric ocular insert of a mucoadhesive polymer that is biocompatible with the ocular surface and tear film of the eye can increase the dissolution time of the polymeric ocular insert. The biodegradable polymers comprising the ocular inserts increase dissolution time on the ocular surface to achieve longer-lasting relief, which can reduce dosing frequency and patient burden typically associated with topical drop administration. These polymeric ocular inserts may also contain one or more pharmaceutically active agents.

The insert also has a thickness and resiliency that is relatively comfortable for the user. The preferred thickness is between 50 and 250 microns, and the most preferred thickness is between 70 and 150 microns. For films that dissolve in less than 2 hours, the target thickness is 90 microns

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the laboratory procedures are well known and commonly employed in the art. Conventional methods are used for these procedures, such as those provided in the art and various general references. When terms are provided in the singular, the inventors also contemplate the plural of the terms. The nomenclature used herein and the laboratory procedures described below are those well known and commonly employed in the art.

As used herein, "about" means that the number referred to as "about" includes the recited number plus or minus 1% -10% of that recited number.

As used herein, "dissolution time" refers to the time taken for the insert to completely dissolve (i.e., decompose from the solid, gel-like material in the carrier under specified conditions to form a homogeneous solution). Dissolution times were measured by the procedure described herein: a 6mm diameter membrane disc was cut and placed in a separate 4ml vial. DI water (2ml) was added to each vial and capped. Each vial was shaken vigorously by hand until the insert was visually detected to have dissolved. The dissolution time was recorded. Here, "hard" is defined as shaking the vial about 90 times per minute and with an up-down amplitude of about 3.5 feet per shaking. Shaking up and down once was counted as shaking twice.

The biodegradable polymer increases the dissolution time of the polymer ocular insert by at least 15% as compared to a control polymer ocular insert that is the same polymer ocular insert except for the absence of the biodegradable polymer, wherein the phrase "percent increase in dissolution time" refers to the formula:

percent increase in dissolution time { [ T ]_{Biodegradable polymers}-T_Control]/T_Control}X 100％

Wherein: t is_{Biodegradable polymers}Is the dissolution time of the insert comprising the biodegradable polymer.

T_{Control of}Is the dissolution time of a control insert (an ocular insert of the same polymer except in the absence of the biodegradable polymer).

Embodiments of the present disclosure provide a polymeric ocular insert that includes an ocular lubricant. In embodiments of the present disclosure, the polymeric ocular insert may be composed of a biodegradable polymer, hyaluronic acid, hydroxypropyl guar (HP guar), and a plasticizer (e.g., polyethylene glycol (PEG)); however, other polymers and plasticizers/softeners may be used without departing from the present disclosure, as described herein. Inserts according to embodiments of the present disclosure may be inserted into the lower eyelid (also known as the fornix) of the eye, and upon insertion, the insert may rapidly absorb tears and dissolve to release ocular lubricant into the tear film to lubricate and protect the ocular surface for an extended period of time as compared to previously known topical ophthalmic compositions. In accordance with embodiments of the present disclosure, a pharmaceutically active agent may also be incorporated into the polymeric ocular insert. Inserting polymeric ocular inserts according to embodiments of the present disclosure may alleviate dry eye symptoms and other ocular conditions in patients.

The biomaterial used to form the polymeric ocular insert according to embodiments of the present disclosure may be comprised of one or more polymers that are biocompatible with the ocular surface and tear film. Polymers that may be used in polymeric ocular inserts according to embodiments of the present disclosure include, but are not limited to, for example, hyaluronic acid (acid or salt form), hydroxypropyl methylcellulose (HPMC), methylcellulose, Tamarind Seed Polysaccharide (TSP), galactomannan; guar and its derivatives, such as hydroxypropyl guar (HP guar), scleroglucan poloxamer, poly (galacturonic) acid, sodium alginate, pectin, xanthan gum, xyloglucan gum, chitosan, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, carbomer, polyacrylic acid, and/or combinations thereof.

Preferred biocompatible polymers are hyaluronic acid, guar gum and derivatives thereof and/or combinations thereof. Hyaluronic acid is an unsulfated glycosaminoglycan, consisting of repeating disaccharide units of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA) linked together by alternating β -1,4 and β -1,3 glycosidic bonds. Hyaluronic acid is also known as hyaluronic acid, hyaluronate, or HA. As used herein, the term "hyaluronic acid" also includes hyaluronic acid in the form of a salt, such as sodium hyaluronate. The preferred hyaluronic acid is sodium hyaluronate. The weight average molecular weight of the hyaluronic acid used in the insert of the invention may vary, but is typically between 0.1 and 2.0 million daltons. In one embodiment, the hyaluronic acid has a weight average molecular weight of 0.5 to 1 million daltons. In another embodiment, the hyaluronic acid has a weight average molecular weight of 1.5 to 2.0 million daltons.

The galactomannans of the present invention may be obtained from a number of sources. Such sources include fenugreek gum, guar gum, locust bean gum, and tara gum. In addition, galactomannans may also be obtained by classical synthetic routes or may be obtained by chemical modification of naturally occurring galactomannans. As used herein, the term "galactomannan" refers to a polysaccharide derived from the above-described natural gums or similar natural or synthetic gums that contains mannose or galactose moieties or both groups as the major structural components. Preferred galactomannans of the present invention are comprised of a linear chain of (1-4) - β -D-mannopyranosyl units and α -D-galactopyranosyl units attached through a (1-6) linkage. For preferred galactomannans, the ratio of D-galactose to D-mannose varies, but generally will be from about 1:2 to 1: 4. Galactomannans have a D-galactose: a D-mannose ratio of about 1:2 is most preferred. In addition, other chemically modified variants of the polysaccharide are also included in the definition of "galactomannan". For example, the galactomannans of the present invention may be substituted with hydroxyethyl, hydroxypropyl and carboxymethylhydroxypropyl groups. Nonionic variants of galactomannans, such as those containing alkoxy and alkyl (C1-C6) groups, are particularly preferred (e.g., hydroxypropyl substitution) when a soft gel is desired. Substitution of non-cis hydroxyl positions is most preferred. An example of a nonionic substitution of the galactomannans of the present invention is hydroxypropyl guar, which has a molar substitution of about 0.4. The galactomannans may also be anionically substituted. Anionic substitution is particularly preferred when a strongly responsive gel is desired, and the preferred galactomannans of the present invention are guar and hydroxypropyl guar. Hydroxypropyl guar is particularly preferred. In the inserts of the invention, the weight average molecular weight of the hydroxypropyl guar may vary, but is typically from 1 to 5 million daltons. In one embodiment, the hydroxypropyl guar has a weight average molecular weight of 2 to 4 million daltons. In another embodiment, the hydroxypropyl guar has a weight average molecular weight of 3 to 4 million daltons.

The polymer used in the insert according to embodiments of the present disclosure should be non-toxic and capable of dissolving in the ocular fluid to ensure that the insert is finally dissolved in a time frame of 60 minutes. It will be appreciated that the polymer(s) selected should be mucoadhesive. It should also be understood that one or more polymers may be blended in accordance with embodiments of the present disclosure. For example, in embodiments of the present disclosure, Hyaluronic Acid (HA) may be mixed with Tamarind Seed Polysaccharide (TSP), as TSP HAs been shown to increase the residence time of HA in the aggregate mixture, and the mixture HAs desirable film mechanical and lubricating properties.

In other embodiments of the present disclosure, hyaluronic acid may be combined with HP guar, as described in further detail below.

In another embodiment of the present disclosure, the polymeric ocular insert further comprises a biodegradable polymer, wherein the biodegradable polymer increases the dissolution time of the polymeric ocular insert by at least 15% compared to a control polymeric ocular insert that is otherwise the same polymeric ocular insert except for the absence of the biodegradable polymer.

The biodegradable polymer is present in the polymeric insert in an amount sufficient to increase the dissolution time of the polymeric eye insert by at least about 15%, preferably at least about 25%, more preferably at least about 35% as compared to a control polymeric eye insert (an otherwise identical polymeric eye insert except for the absence of the biodegradable polymer).

Any type of biodegradable polymer may be used herein, such as polyglycolic acid (PGA), Polyhydroxybutyrate (PHB), polyhydroxybutyrate-beta-hydroxyvalerate copolymer (PHBV), polycaprolactone (pcl), nylon-2-nylon-6, polylactic acid (PLA), poly (lactic-co-glycolic) acid (PLGA), and poly (caprolactone). Preferred biodegradable polymers of the present application are polylactic acid (PLA), poly (lactic-co-glycolic) acid (PLGA), or poly (caprolactone). More preferred biodegradable polymers are polylactic acid, poly (lactic-co-glycolic) acid. Even more preferred biodegradable polymers are poly (lactic-co-glycolic) acid copolymers (PLGA). Biodegradable polymers are a particular class of polymers that can be broken down by bacterial decomposition processes to produce natural byproducts, such as gases (CO2, N2), water, biomass, and inorganic salts, after achieving their intended purpose. These polymers were found to be both natural and synthetic and largely comprised of ester, amide, and ether functional groups. Their nature and mechanism of decomposition are determined by their exact structure. These polymers are typically synthesized by condensation reactions, ring opening polymerizations, and metal catalysts. There are a large number of examples and applications of biodegradable polymers. In the past decades, bio-based packaging materials have been introduced as green alternative materials in which edible films have gained more attention due to their environmentally friendly characteristics, wide variety, practicality, non-toxicity, and low cost.

One of the most commonly used biodegradable polymers for packaging purposes is polylactic acid (PLA). The production of PLA has several advantages, the most important of which is the ability to tailor the physical properties of the polymer through the processing method. PLA is used in various films, packaging materials, and containers (including bottles and cups). In 2002, the FDA regulated PLA to be safe in all food packages.

Preferred biodegradable polymers of the present application are lactic acid copolymers; as used herein, "lactic acid copolymer" generally means a copolymer comprising lactic acid units and glycolic acid units (PLGA). However, malic acid, glyceric acid, tartaric acid, or the like may also be used instead of glycolic acid. "lactic acid copolymer" also includes copolymers comprising lactic acid units in a 100% molar ratio, i.e., poly (lactic acid). The lactic acid unit may be in the L-, D-, or DL-form.

When preparing an ocular insert, PLGA (commercially available from polymer sciences, Inc.) is added to the insert taking into account the ratio of lactic acid units and glycolic acid units and the molecular weight of the copolymer (commercially available). The molar content of lactic acid units in the copolymer for use in the ocular insert of the present application is preferably from 50% to 100%. The molar content of glycolic acid units is preferably 0 to 50%. The molecular weight of the copolymer affects the tensile strength of the ocular insert. The tensile strength of the ocular insert increases with increasing molecular weight as compared to adding the same amount of PLGA biodegradable polymer to the ocular insert. For the purposes of this application, the molecular weight of the copolymer is preferably 10,000 or greater, but preferably 1,000,000 or less. Therefore, the weight average molecular weight of the PLGA copolymer is preferably from 10,000 to 1,000,000. The ratio of lactic acid units and glycolic acid units ranges from 100/0 to 50/50, taking into account the dissolution time of the ocular insert, compared to adding the same amount of PLGA to the ocular insert.

In some embodiments, the biodegradable polymer is present in an amount from about 0.5% to about 10%, from about 1% to about 5%; one or more mucoadhesive polymers are present in an amount from about 50% w/w to about 95% w/w, about 60% w/w to about 90% w/w, about 70% w/w to about 85% w/w, or about 80% w/w to about 90% w/w by dry weight of the polymeric ocular insert, provided that the sum of the% w/w of the mucoadhesive polymer and the% w/w of the biodegradable polymer and other components not listed above is 100% w/w.

The total dry weight or mass of the polymeric ocular insert may range from about 1mg to about 10mg, or from about 2mg to about 8mg, and in particular embodiments, may be from about 2.5mg to about 5 mg.

In some embodiments of the present disclosure, softeners and/or plasticizers may be added to one or more polymers to help make softer, more moldable delivery systems, and also to provide improved comfort upon insertion. Plasticizers can soften the material to provide a desired rate of dissolution. It is to be understood that the softener and/or plasticizer may be a low or high molecular weight compound, including but not limited to: polyethylene glycol (PEG) and derivatives thereof, water, vitamin E and triethyl citrate.

In some embodiments, the plasticizer or softening agent is present in an amount from about 2% w/w to about 25% w/w, about 5% w/w to about 20% w/w, about 5% w/w to about 15% w/w, or about 5% w/w to about 10% w/w by dry weight of the polymeric ocular insert, provided that the sum of the% w/w of the mucoadhesive polymer and the% w/w of the biodegradable polymer and other components not listed above is 100% w/w.

In some embodiments, the polymeric ocular insert may have a moisture content of about 1% to about 50% after hydration. In particular embodiments, the polymeric ocular insert may have a moisture content of 30% -40%.

The polymeric ocular insert can be of any size or shape suitable for application to the eye. Exemplary shapes include a film, a rod, a sphere, or an irregular shape having a maximum size in any single dimension of 5-6 mm.

In some embodiments, the polymeric eye insert has a thickness of about 50-400 μm, about 100-300 μm, about 150-250 μm, or about 200 μm.

In a particular embodiment, the polymeric ocular insert has a thickness of about 150 and 250 μm, and a moisture content of 30% w/w to 50% w/w.

In some embodiments of the present disclosure, the polymeric ocular insert does not include an additional pharmaceutically active agent. In other embodiments, the polymeric ocular insert may include one or more additional pharmaceutically active agents. In some embodiments, the one or more pharmaceutically active agents may be selected from the group consisting of: ocular lubricants, anti-redness agents such as alpha-2 adrenergic agonists (e.g., brimonidine, arabicola, etc.), sympathetic excitomotors such as tetrahydrozoline, naphazoline, TRPM8 agonists such as menthol, menthol analogs, steroidal and non-steroidal anti-inflammatory drugs for relief of ocular pain and inflammation, antibiotics, antihistamines such as olopatadine, antivirals, antibiotics and antimicrobials for infectious conjunctivitis, antimuscarinics such as atropine and its derivatives for treatment of myopia, and glaucoma drug delivery such as prostaglandins and prostaglandin analogs (e.g., travoprost), or therapeutically suitable combinations thereof.

Polymeric ocular inserts according to embodiments of the present disclosure may be manufactured using various processing techniques, including but not limited to compression molding and solution casting. Compression molding can be performed at temperatures and pressures that do not change the material or cause significant side effects. For example, compression molding of partially hydrated polysaccharide may be performed at about 200-300 degrees Celsius using about 5,000-12,000 pounds of compression force for about 1-2 minutes. Solution or film casting may be performed using solvents and/or co-solvents that may provide uniform films with few defects. The solvent may be removed by air drying or vacuum drying, thereby allowing the insertion material to be free of residual solvent. For example, a 1% (w/v) aqueous solution of the polymer (or mixture) may be cast and then allowed to evaporate. The film can then be cut with an elliptical punch of the desired size and geometry. While compression molding and solution/film casting have been described, it is understood that other processing techniques may be used without departing from the disclosure.

In one embodiment, the film casting method used was found to produce reproducible inserts and good structural integrity. In this example, distilled water was placed in a 1L Erlenmeyer flask, and then the polymer(s) were added. The flask was placed in an ultrasonic generator and attached to an overhead mechanical stirrer. The mixture was sonicated at 30 ℃ and stirred for 60 minutes. The speed of the mechanical stirrer was adjusted to 700rpm and allowed to stir for 60 minutes. The stirring was stopped and the plasticizer (PEG and/or PVP) was added to the flask. This mixture was stirred at 700rpm for 30 minutes at 30 ℃ under sonication until a homogeneous, clear solution was obtained. The mechanical agitation was then stopped and sonication was allowed to continue for an additional 30 minutes in order to remove all bubbles. The Erlenmeyer flask was then removed from the sonicator and allowed to stand at room temperature for 30 minutes. To prepare the membrane, a petri dish (diameter 150 mm. times.height 15mm) was filled with about 150 g. + -.2 g of stock solution. The stock solution was evaluated by different evaporation techniques. In a first experiment, a vacuum oven at 50 ℃ was used. The petri dish was placed in an oven, and the oven was evacuated using a vacuum pump. After 30 hours, the obtained films were yellow and some of these films showed curved surfaces. The experiment was repeated at 45 ℃, 40 ℃ and 35 ℃ under the same vacuum conditions. All of the above experimental conditions produced colored films or films with uneven weight distribution. It was also observed that the higher the temperature, the darker and more intense the yellow color became. The preferred evaporation technique involves evaporation at room temperature in a chamber equipped with a variable speed exhaust. During the evaporation process, air flow, temperature and humidity are all measured. The techniques described above can produce uniform evaporation and films with consistent thickness.

As previously mentioned, in vivo studies have shown that conventional topical ophthalmic lubricants do not remain in the eye for more than about 25 minutes. However, the use of one or more polymers in combination with a plasticizer/softener, such as mixing HP guar and hyaluronic acid with a plasticizer (such as PEG), can provide a flexible membrane with adjustable hydration and dissolution rates to achieve comfortable insertion. While certain embodiments of the present invention are polymeric ocular inserts comprising a mixture of hyaluronic acid, HP guar, and PEG, it is understood that other mixtures may be used with polymeric ocular inserts according to other embodiments of the present disclosure.

The ocular inserts of the present disclosure are platforms for delivery of lubricants and other pharmaceutically active agents to treat ocular surface symptoms such as redness, itching, and dry eyes. In some embodiments, the polymeric ocular insert may be used to prolong contact of a pharmaceutically active agent or prolong drug delivery of a pharmaceutically active agent to the eye. Thus, in some embodiments, the present disclosure provides a method of prolonging drug delivery or prolonging contact of a pharmaceutically active agent to the eye if: administering to a patient in need thereof a polymeric ocular insert comprising a pharmaceutically active agent.

In some embodiments, the present disclosure provides a method of treating or alleviating the signs and/or symptoms of dry eye disease (keratoconjunctivitis sicca) comprising administering to a patient in need thereof a polymeric ocular insert according to the present disclosure.

The following non-limiting examples are provided to illustrate embodiments of the present invention.

Examples of the invention

Example 1-polymeric ocular inserts containing alpha-2-adrenergic agonists

In other inventions, insertion membranes were prepared using alpha-2 adrenergic receptor agonists (e.g., brimonidine) at different concentrations, i.e., 90ppm, 495ppm, and 5048ppm, respectively.

Preparation of control insert membrane brimonidine:

300mL of DI water was transferred from the graduated cylinder to a clean 500mL Erlenmeyer flask. HA (0.94g) and PVP (0.21g) were added to a 500ml Erlenmeyer flask. Stirring the mixture

After 1.5 hours, a homogeneous solution was obtained. HP guar (0.84g) was added and

the mixture was stirred for 1 hour, so that the mixture was again homogeneous. PEG (0.21g) was added and the mixture was stirred for an additional 30 min. The mixture was then allowed to stand

(without stirring) for 30min to remove air bubbles. The mixture (150g) was poured into a petri dish (petridish),

the dishes were then placed in an evaporation oven (27. + -. 3 ℃) for 2 days to produce a membrane.

Insertion membrane hydration procedure: the film was cut into 6mm discs with a disc cutter. Note that: the thickness of each disc was measured prior to hydration. Two discs were placed in the middle of the bag, with 3 μ l of DI water at the bottom corner of the bag. The bag was sealed with a heat sealer.

Preparation of a film containing 100ppm brimonidine tartrate

The initial phase was performed following the procedure for preparing the control insert in membrane brimonidine. After adding PEG and stirring for 30min, a solution of 2ml of 0.52mg/ml brimonidine tartrate in DI water was added and the mixture was stirred for 15 min. All remaining steps were performed as detailed above in the membrane preparation/hydration section.

Preparation of a film containing 500ppm brimonidine tartrate

The initial phase was performed following the procedure for preparing the control insert in membrane brimonidine. After adding PEG and stirring for 30min, 0.4ml of a 0.52mg/ml solution of brimonidine tartrate in DI water was added and the mixture was stirred for 15 min. All remaining steps were performed as detailed above in the membrane preparation/hydration section.

Preparation of a Membrane containing 5000ppm brimonidine tartrate

The initial phase was performed following the procedure for preparing the control insert in membrane brimonidine. After adding PEG and stirring for 30min, a solution of 1.06mg/ml brimonidine tartrate in 10ml DI water was added and the mixture was stirred for 15 min. All remaining steps were performed as detailed above in the membrane preparation/hydration section.

Measurement of different film properties of brimonidine tartrate films and current formulation films

A series of physical properties of brimonidine tartrate doped films were measured. The procedure for each property measurement is summarized below, and the results are summarized in table 1.

Dissolving time:

a 6mm diameter membrane disc was cut and placed in a separate 4ml vial. DI water (2ml) was added to each vial and capped. Each vial was shaken vigorously by hand until the insert was visually detected to have dissolved. The dissolution time was recorded.

Formulation Ph:

after obtaining a homogeneous formulation solution, the solution pH was measured using an oaklon pH meter.

And (3) mechanical testing:

strips of 1-1.5x4cm film were cut and then hydrated in separate sealed aluminum foil bags containing 60 μ L DI water for 36-48 hours. The resulting hydrated film tape was then subjected to mechanical testing using an Instron testing machine [ Young's modulus and% elongation at break ]. Presented in table 1 below is a summary of the physical characterization of the properties of the inserted films.

The mechanical stability of the inserted films containing brimonidine was tested at 25 ℃ and 37 ℃ at time zero (time zero) and is shown in table 2 below. The insert film containing brimonidine showed excellent mechanical stability at 25 ℃ and 37 ℃ for 45 days. Wet caliper increases moderately over time compared to zero.

Example 2-polymeric PLGA-containing eye inserts

Evaluation PLGA (MW: 10,000 to 18,000 and 96,000) was added to polymer insert compositions at different concentrations (1%, 1.7%, 2% and 4%). PLGA doped membranes show a similar spectrum as undoped membranes. The presence of PLGA slows the dissolution rate and does not cause significant changes to the mechanical properties of the membrane. PLGA concentration and molecular weight have a significant effect on the dissolution profile.

PLGA solubility screening:

low or high MW PLGA was found to be insoluble in DI water, ethanol, pentanol, methanol and PEG 400. Low or high MW PLGA was found to be soluble in DCM, THF, EA and acetone. Both low and high MW PLGA will be introduced into the current formulation as a solution in acetone.

Preparation of control insert membrane _ PLGA:

300mL of DI water was transferred from the graduated cylinder to a clean 500mL Erlenmeyer flask. HA (0.84g) and PVP (0.21g) were added to a 500mL Erlenmeyer flask. After stirring the mixture for 1.5 hours, a homogeneous solution was obtained. HP guar (0.84g) was added and the mixture was stirred for 1 hour before the mixture was again made homogeneous. PEG (0.21g) was added and the mixture was stirred for an additional 30 minutes. The mixture was then allowed to stand (without stirring) for 30min to remove air bubbles. The mixture (150g) was poured into a petri dish, which was then placed in an evaporation oven (27 + -3 deg.C) for 2 days to produce a membrane.

Preparation of membranes comprising 1.7% low MW PLGA:

the initial phase was performed following the procedure for preparing the control insert in membranous _ PLGA. After PEG was added and stirred for 30min, 2.2ml of 81.4mg/5ml low MW PLGA solution in acetone was added and the mixture was stirred for 30 min. All remaining steps were performed as detailed in the insert preparation section.

Preparation of membranes comprising 0.94% high MW PLGA:

the initial phase was performed following the procedure for preparing the control insert in membrane PLGA. After adding PEG and stirring for 30min, 1.1ml of a 90mg/5ml solution of high MW PLGA in acetone was added and the mixture was stirred for 30 min. All remaining steps were performed as detailed in the insert preparation section.

Preparation of membranes comprising 1.94% low MW PLGA:

the initial phase was performed following the procedure for preparing the control insert in membrane PLGA. After PEG addition and stirring for 30min, 10ml of a 4.08mg/ml low MW PLGA solution in acetone was added and the mixture was stirred for 1.5 hours. The solution was slightly cloudy. All remaining steps were performed as detailed in the insert preparation section.

Preparation of a membrane comprising 2.02% high MW PLGA:

the initial phase was performed following the procedure for preparing the control insert in membrane PLGA. After adding PEG and stirring for 30min, 10ml of a 4.25mg/ml solution of high MW PLGA in acetone was added and the mixture was stirred for 1.5 hours. The solution was turbid. All remaining steps were performed as detailed in the insert preparation section.

Preparation of films comprising 4.07% low MW PLGA:

the initial phase was performed following the procedure for preparing the control insert in membranous _ PLGA. After PEG addition and stirring for 30min, 10ml of a 8.55mg/ml solution of high MW PLGA in acetone was added and the mixture was stirred for 1.5 hours. The solution was turbid. All remaining steps were performed as detailed in the insert preparation section.

Measurement of different film characteristics of PLGA films and films of the current formulation

A series of physical properties were measured for PLGA doped films and current formulation films (funnel test). The procedure for each property measurement is summarized below and the results are summarized in the following table.

Dissolving time:

a 6mm diameter membrane disc was cut and placed in a separate 4ml vial. DI water (2ml) was added to each vial and capped. Each vial was shaken vigorously until the insert was dissolved by visual inspection. The dissolution time was recorded.

Formulation pH:

And (3) mechanical testing:

strips of 1-1.5X4cm film were cut and then hydrated in separate sealed aluminum foil bags containing 30. mu.L of added DI water for 36-48 hours. The resulting hydrated film tape was then subjected to mechanical testing using an Instron testing machine [% young's modulus and% elongation at break ].

Summarized below are the results of the test parameters for different PLGA-doped membranes:

example 11-polymeric ocular inserts comprising TRPM8 agonist (menthone glycerol ketal)

Evaluation MGA was added to the polymer insert composition at 20ppm and 40 ppm. MGA doped films exhibited similar color and transparency as undoped films. The presence of MGA significantly altered the folding durability results. The MGA-doped dry film developed cracks/fractures after less than 20 folding cycles. In contrast, both doped and undoped hydrated films exhibited similar folding durability characteristics.

Preparation of control insert membrane _ MGA:

800ml of DI water was transferred from a graduated cylinder to a clean 1000ml conical flask. HA (2.24g) and PVP (0.56g) were added to a 1000ml Erlenmeyer flask. The mixture was stirred by mechanical stirring and simultaneously sonicated. After a total of 1.5 hours, the mixture was observed to be homogeneous. HP guar (2.24g) was added and the mixture was again stirred while sonicating. After 1 hour, the mixture was again homogeneous. PEG (0.56g) was added and the mixture was stirred and sonicated for an additional 30 min. The stirring was then stopped. The mixture was allowed to continue to sonicate for an additional 30min to remove air bubbles. After sonication, the mixture was allowed to stand on the bench for 30 min. The mixture (150g) was poured into a petri dish (petri dish). The film was formed after 2 days of evaporation in an oven at 27+ -3 ℃.

Insertion membrane hydration procedure: the film was cut into 6mm discs with a disc cutter. Note that: the thickness of each disc was measured prior to hydration. Two discs were placed in the middle of the bag, with 3 μ l of DI water at the bottom corner of the bag. The bag is sealed with a sealer.

Preparation of a film containing 20ppm MGA:

the initial stage of the above film preparation procedure was followed. After addition of PEG and stirring/sonication for 30min, 140. mu.l of a 0.84mg/ml MGA solution in DI water-MeOH (2/1) was added and the mixture was stirred while sonicated for 15 min. All remaining steps were performed as detailed in the membrane preparation procedure.

Preparation of a film containing 40ppm MGA:

the initial stage of the above membrane preparation procedure was followed. After addition of PEG and stirring/sonication for 30min, 280. mu.l of a 0.84mg/ml MGA solution in DI water-MeOH (2/1) was added and the mixture was stirred while sonicated for 15 min. All remaining steps were performed as detailed in the membrane preparation procedure. Summarized below are the physical test results of MGA doped films.

Measurement of different film properties of MGA-doped and currently formulated films

Different membrane properties were measured for MGA doped membranes and current formulation membranes (funnel test). The procedure for each property measurement is summarized below, and the results are summarized in the following table.

Dissolving time:

Formulation pH:

And (3) mechanical testing:

a 1x4cm film strip was cut and then hydrated in a separate sealed aluminum foil pouch containing 60 μ L of added DI water for 24 hours. The resulting hydrated film tape was then subjected to mechanical testing using an Instron [ young's modulus and% elongation at break ].

Claims

1. A polymeric ocular insert, the insert comprising: a biodegradable polymer and one or more mucoadhesive polymers that are biocompatible with the ocular surface and tear film of the eye; wherein the biodegradable polymer increases the dissolution time of the polymer ocular insert by at least 15% compared to a control polymer ocular insert that is otherwise identical except for the absence of the biodegradable polymer.

2. The polymeric ocular insert of claim 1, wherein the biodegradable polymer is PLGA or PLA.

3. The polymeric ocular insert of claim 2, wherein the biodegradable polymer is PLGA.

4. The polymeric ocular insert of claim 1, wherein the one or more mucoadhesive polymers are selected from the group comprising: hyaluronic acid or a salt thereof, hydroxypropyl methylcellulose (HPMC), methylcellulose, Tamarind Seed Polysaccharide (TSP), guar gum, hydroxypropyl guar gum (HP guar), scleroglucan poloxamer, poly (galacturonic) acid, sodium alginate, pectin, xanthan gum, xyloglucan gum, chitosan, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carbomer, polyacrylic acid, and combinations thereof.

5. The polymeric ocular insert of claim 1, wherein the biodegradable polymer is present in an amount from 0.5% w/w to 10% w/w.

6. The polymeric ocular insert of claim 4, wherein the one or more mucoadhesive polymers is HP guar, hyaluronic acid, sodium hyaluronate, or polyvinylpyrrolidone.

7. The polymeric ocular insert of claim 1, wherein the one or more mucoadhesive polymers are present in an amount from about 50% w/w to about 90% w/w, about 60% w/w to about 85% w/w, about 70% w/w to about 85% w/w, or about 80% w/w to about 90% w/w of the polymeric ocular insert, provided that the sum of% w/w of mucoadhesive polymers and% w/w of the biodegradable polymers and other components not listed above is 100% w/w.

8. The polymeric ocular insert of claim 1, further comprising a plasticizer or softener.

9. The polymeric ocular insert of claim 8, wherein the plasticizer or softening agent is selected from the group comprising: polyethylene glycol (PEG), PEG derivatives, water, vitamin E and triethyl citrate.

10. The polymeric ocular insert of claim 8, wherein the plasticizer or softening agent is present in an amount from about 2% w/w to about 25% w/w, about 5% w/w to about 20% w/w, about 5% w/w to about 15% w/w, or about 5% w/w to about 10% w/w of the polymeric ocular insert, provided that the sum of% w/w of mucoadhesive polymer and% w/w of the biodegradable polymer, the% w/w of the plasticizer or softening agent, and the% w/w of other components not listed above is 100% w/w.

11. The polymeric ocular insert of claim 9, wherein the plasticizer or softening agent is PEG.

12. The polymeric eye insert of any one of the preceding claims, wherein the control insert consists of about 38.5% w/w HP guar, about 9.5% w/w PVP, about 38.5% w/w sodium hyaluronate, 5% w/w PLGA and about 9.5% PEG.

13. The polymeric ocular insert of claim 1, further comprising 1-5000ppm of an alpha-2 adrenergic receptor agonist.

14. The polymeric ocular insert of claim 1, further comprising 10-100ppm menthone glycerol ketal.

15. The polymeric ocular insert of claim 1, wherein the insert shape is a membrane, a rod, a sphere, a ring, or an irregular shape having a maximum size in any single dimension of 5-6 mm.